Nongenotoxic 3-nitroimidazo[1,2-a]pyridines are NTR1 substrates that display potent in vitro antileishmanial activity

2019

Article référencé dans le Web of Science WOS:000455561600005

Fersing C., Basmaciyan L., Boudot C., Pedron J., Hatter S., Cohen A., Castera-Ducros C., Primas N., Laget M., Casanova M., Bourgeade-Delmas Sandra, Piednoel M., Sournia-Saquet A., Mbou V. B., Courtioux B., Boutet-Robinet E., Since M., Milne R., Wyllie S., Fairlamb A. H., Valentin A., Rathelot P., Verhaeghe P., Vanelle P., Azas N.

ACS Medicinal Chemistry Letters, 2019, 10 (1), p. 34-39 ISSN 1948-5875

Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 mu M) alongside good antileishmanial activities (IC50 = 1-2.1 mu M) against L. donovani, L. infantum, and L. major; and good antitrypanosomal activities (IC50 = 1.3-2.2 mu M) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC50 = 0.6 to 13.3 mu M). Molecule 5, presenting a low reduction potential (E degrees = -0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making 5 a good candidate for further in vivo studies.

Sciences fondamentales / Techniques d'analyse et de recherche [020] ; Santé : généralités [050] ; Entomologie médicale / Parasitologie / Virologie [052]

Fonds IRD [F B010074883]

fdi:010074883